CN111362824B - Process for the preparation of 2- (aminomethyl) -N, N-diethyl-1-phenylcyclopropanecarboxamide and salts thereof - Google Patents
Process for the preparation of 2- (aminomethyl) -N, N-diethyl-1-phenylcyclopropanecarboxamide and salts thereof Download PDFInfo
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- CN111362824B CN111362824B CN201811593395.5A CN201811593395A CN111362824B CN 111362824 B CN111362824 B CN 111362824B CN 201811593395 A CN201811593395 A CN 201811593395A CN 111362824 B CN111362824 B CN 111362824B
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- 238000000034 method Methods 0.000 title claims abstract description 30
- 150000003839 salts Chemical class 0.000 title claims abstract description 22
- GJJFMKBJSRMPLA-UHFFFAOYSA-N milnacipran Chemical compound C=1C=CC=CC=1C1(C(=O)N(CC)CC)CC1CN GJJFMKBJSRMPLA-UHFFFAOYSA-N 0.000 title claims abstract description 7
- 238000002360 preparation method Methods 0.000 title description 14
- GJJFMKBJSRMPLA-HIFRSBDPSA-N (1R,2S)-2-(aminomethyl)-N,N-diethyl-1-phenyl-1-cyclopropanecarboxamide Chemical compound C=1C=CC=CC=1[C@@]1(C(=O)N(CC)CC)C[C@@H]1CN GJJFMKBJSRMPLA-HIFRSBDPSA-N 0.000 claims abstract description 59
- 229960000600 milnacipran Drugs 0.000 claims abstract description 57
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 43
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 37
- 239000003960 organic solvent Substances 0.000 claims description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 32
- 239000000243 solution Substances 0.000 claims description 28
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 22
- 239000011259 mixed solution Substances 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000010410 layer Substances 0.000 claims description 20
- 239000007787 solid Substances 0.000 claims description 20
- 239000012046 mixed solvent Substances 0.000 claims description 19
- 238000010992 reflux Methods 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 18
- 229940011051 isopropyl acetate Drugs 0.000 claims description 15
- 238000001816 cooling Methods 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000012044 organic layer Substances 0.000 claims description 11
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 8
- 229910052700 potassium Inorganic materials 0.000 claims description 8
- 239000011591 potassium Substances 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- 239000012279 sodium borohydride Substances 0.000 claims description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- 239000012448 Lithium borohydride Substances 0.000 claims description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 6
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000005456 alcohol based solvent Substances 0.000 claims description 4
- 150000001298 alcohols Chemical group 0.000 claims description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 4
- -1 sodium triacetoxyborohydride Chemical compound 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 3
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 239000003759 ester based solvent Substances 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- XNCDYJFPRPDERF-PBCQUBLHSA-N Milnacipran hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1[C@@]1(C(=O)N(CC)CC)C[C@@H]1C[NH3+] XNCDYJFPRPDERF-PBCQUBLHSA-N 0.000 abstract description 15
- 229960000638 milnacipran hydrochloride Drugs 0.000 abstract description 15
- 230000007613 environmental effect Effects 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000012535 impurity Substances 0.000 abstract description 3
- 238000003756 stirring Methods 0.000 description 36
- WNZQDUSMALZDQF-UHFFFAOYSA-N 2-benzofuran-1(3H)-one Chemical compound C1=CC=C2C(=O)OCC2=C1 WNZQDUSMALZDQF-UHFFFAOYSA-N 0.000 description 18
- 239000012043 crude product Substances 0.000 description 18
- 238000001914 filtration Methods 0.000 description 18
- 239000000047 product Substances 0.000 description 17
- 239000007864 aqueous solution Substances 0.000 description 16
- 239000006227 byproduct Substances 0.000 description 12
- 238000001035 drying Methods 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- AKPUJVVHYUHGKY-UHFFFAOYSA-N hydron;propan-2-ol;chloride Chemical compound Cl.CC(C)O AKPUJVVHYUHGKY-UHFFFAOYSA-N 0.000 description 9
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 8
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 230000001430 anti-depressive effect Effects 0.000 description 4
- 239000000935 antidepressant agent Substances 0.000 description 4
- 229940005513 antidepressants Drugs 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 231100000331 toxic Toxicity 0.000 description 4
- 230000002588 toxic effect Effects 0.000 description 4
- FCVIWMMSEWILOP-UHFFFAOYSA-N 2-n,2-n-dimethylbenzene-1,2-dicarboxamide Chemical compound CN(C)C(=O)C1=CC=CC=C1C(N)=O FCVIWMMSEWILOP-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 150000002596 lactones Chemical class 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 2
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 description 2
- 208000020401 Depressive disease Diseases 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- LFETXMWECUPHJA-UHFFFAOYSA-N methanamine;hydrate Chemical compound O.NC LFETXMWECUPHJA-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229960002748 norepinephrine Drugs 0.000 description 2
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 2
- 125000005544 phthalimido group Chemical group 0.000 description 2
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000007142 ring opening reaction Methods 0.000 description 2
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- XNCDYJFPRPDERF-UHFFFAOYSA-N 2-(aminomethyl)-n,n-diethyl-1-phenylcyclopropane-1-carboxamide;hydron;chloride Chemical compound Cl.C=1C=CC=CC=1C1(C(=O)N(CC)CC)CC1CN XNCDYJFPRPDERF-UHFFFAOYSA-N 0.000 description 1
- JOTWZGIFEGRKFM-UHFFFAOYSA-N 2-[(1,3-dioxoisoindol-2-yl)methyl]-n,n-diethyl-1-phenylcyclopropane-1-carboxamide Chemical compound C1C(CN2C(C3=CC=CC=C3C2=O)=O)C1(C(=O)N(CC)CC)C1=CC=CC=C1 JOTWZGIFEGRKFM-UHFFFAOYSA-N 0.000 description 1
- 229940122200 5 Hydroxytryptamine uptake inhibitor Drugs 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000007590 Disorders of Excessive Somnolence Diseases 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- 102000000543 Histamine Receptors Human genes 0.000 description 1
- 108010002059 Histamine Receptors Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 102000010909 Monoamine Oxidase Human genes 0.000 description 1
- 108010062431 Monoamine oxidase Proteins 0.000 description 1
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 1
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 208000022371 chronic pain syndrome Diseases 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 206010013990 dysuria Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 238000006698 hydrazinolysis reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 206010020765 hypersomnia Diseases 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 239000002767 noradrenalin uptake inhibitor Substances 0.000 description 1
- 229940127221 norepinephrine reuptake inhibitor Drugs 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a novel method for preparing 2- (aminomethyl) -N, N-diethyl-1-phenylcyclopropanecarboxamide (milnacipran) and salt thereof, which comprises the steps of reducing a compound with a structure shown in a formula (I) by using a reducing agent to obtain milnacipran with a structure shown in a formula (II), and salifying the milnacipran to obtain milnacipran hydrochloride. The method provided by the invention effectively controls the generation of impurities, greatly improves the yield and purity of the product, has the characteristics of environmental protection, safety and economy, is suitable for industrial production, and has wide market application prospect.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a preparation method of 2- (aminomethyl) -N, N-diethyl-1-phenylcyclopropanecarboxamide and salts thereof.
Background
Milnacipran (Milnacipran) is a novel specific 5-hydroxytryptamine and norepinephrine reuptake inhibitor (SNRI), developed by Pierre fabric medical, france, and marketed in 1997 as a drug for the treatment of depression, and was approved by the FDA in the united states for the treatment of fibromyalgia syndrome in 2009. The chemical name of milnacipran is: 2- (Aminomethyl) -N, N-diethyl-1-phenylcyclopropanecarboxamide, having the formula: c 15 H 22 N 2 O, the chemical structural formula is as follows:
at present, the hydrochloride of milnacipran is used clinically, and the chemical name is as follows: 2- (aminomethyl) -N, N-diethyl-1-phenylcyclopropanecarboxamide hydrochloride having the formula: c 15 H 22 N 2 O & HCl, chemical structure as follows:
as a fourth generation antidepressant, milnacipran can simultaneously inhibit reuptake of 5-hydroxytryptamine and norepinephrine by neurons, so that the transmitter concentration in synaptic cleft is increased, and the synaptic transmission function is promoted to play an antidepressant role. Milnacipran has high affinity for 5-hydroxytryptamine and norepinephrine and alpha 1 -adrenoceptor, muscarinic receptor and H 1 The histamine receptor has no affinity and no effect on monoamine oxidase activity. The milnacipran does not participate in the reaction of cytochrome P450 enzyme, so that the milnacipran hardly interacts with other medicines, has better tolerance, and does not have abnormal phenomenon of receptor regulation even if the milnacipran is taken for a long time. Compared with tricyclic and SSRIs antidepressants, the milnacipran has more obvious antidepressant effect, is obviously superior to placebo, has no hypersomnia and anticholinergic effect which are common in tricyclic, has less gastrointestinal adverse reactions such as nausea, vomiting and the like than SSRIs, and has more obvious dysuria and tremor. Milnacipran can be used for acute-phase treatment and maintenance-phase treatment of depression, and can also be used for treating depression after stroke, depression after brain trauma and chronic pain syndrome, and is a promising antidepressant.
At present, a number of documents disclose methods for synthesizing milnacipran and its salts. Patent EP0200638A1 discloses a synthetic route to milnacipran hydrochloride. In the method, phthalimide potassium salt and lactone are reacted to generate a ring-opening product, carboxyl acyl chloride is activated to react with alkylamine, the milnacipran is obtained through hydrazinolysis, and finally the final product milnacipran hydrochloride is obtained through salification. The synthetic route is as follows:
the method uses highly toxic hydrazine reagent, and hydrazine can produce toxic and side effects on liver, kidney, blood, etc. There are data showing that hydrazine may have a carcinogenic effect. Therefore, the use of a large amount of hydrazine reagent puts a great pressure on the safety and environmental protection of operators. In addition, the process has poor yield and purity, and is not suitable for industrial mass production.
Patent application CN101107228A discloses a synthesis method of milnacipran hydrochloride, which comprises the steps of reacting phthalimide potassium salt with lactone to generate phthalimido derivatives, reacting 40% methylamine water solution with the phthalimido derivatives to obtain milnacipran, and salifying with hydrochloric acid to obtain milnacipran hydrochloride. The specific route is as follows:
the problems with this route are: 40% methylamine water solution is used for reaction, the property of the generated by-product N, N-dimethyl phthalic diamide is close to that of the main product, and the generated by-product N, N-dimethyl phthalic diamide is separated out in the reaction liquid and forms a suspension state, so that the by-product N, N-dimethyl phthalic diamide is not easy to separate from the main product, the difficulty of post-treatment is increased, and the obtained product has poor purity and low yield. In addition, methylamine is highly irritant and corrosive, stimulates the respiratory system and the skin, has serious damage to eyes, and is also not suitable for industrial mass production.
In the milnacipran synthesis route disclosed in patent application CN103601652A, lactone firstly reacts with thionyl chloride in an alcoholic solution for ring opening reaction to obtain cis-2-chloromethyl-1-phenyl cyclopropane carboxylic acid methyl ester, then reacts with sodium azide to obtain cis-2-azidomethyl-1-phenyl cyclopropane carboxylic acid methyl ester, and reacts with diethylamine after hydrolysis to obtain cis-N, N-diethyl-2-azidomethyl-1-phenyl cyclopropane carboxamide, and finally the milnacipran is obtained by reduction through Pd/C.
The route adopts sodium azide as a reactant, and the reactant is not only highly toxic, but also is extremely easy to cause explosion, and is not suitable for industrial mass production. In addition, the route uses Pd/C and other metal reducing agents with higher price, so that the process cost is increased, the heavy metal of the product is easy to exceed the standard, and the difficulty in purifying the product is increased.
Therefore, the development of a synthesis process of milnacipran and its salts, which is economical, efficient, high in yield, environmentally friendly, suitable for industrial production and has high purity, is urgently needed.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a preparation method of milnacipran and salt thereof.
The invention provides a preparation method of 2- (aminomethyl) -N, N-diethyl-1-phenylcyclopropanecarboxamide (milnacipran) and salt thereof, which is characterized by comprising the following steps: the method comprises the following steps:
A. taking a compound (I), and reacting in a solvent in the presence of a reducing agent to obtain a mixed solution;
B. adding acid into the mixed solution obtained in the step A for reaction, and purifying the reaction solution to obtain milnacipran with a structure of a formula (II);
further, the solvent in the step A is a mixed solvent of an organic solvent and water;
and/or the volume mass ratio of the mixed solvent to the compound (I) in the step A is 5: 1-20, preferably 8;
and/or, the reducing agent in the step A is borohydride; preferably, the borohydride is one or more selected from sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride;
and/or, the molar ratio of the reducing agent to compound (I) in step a is 1:1 to 5, preferably 1.1:1 to 3;
and/or, the reaction temperature in step a is from 30 ℃ to reflux temperature, preferably from 40 ℃ to reflux temperature.
Further, the organic solvent is selected from alcohols, amides, nitriles, ethers; preferably, the organic solvent is selected from one or more of methanol, ethanol, N-propanol, isopropanol, ethylene glycol, N-butanol, N-dimethylformamide, N-dimethylacetamide, acetonitrile and tetrahydrofuran.
Further, the volume ratio of the organic solvent to water is 1:1 to 30, preferably 3.
Further, the acid in the step B is selected from one or more of hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid and perchloric acid, and hydrochloric acid is preferred;
and/or, the reaction temperature in the step B is 40 ℃ to reflux, preferably 60 ℃ to reflux;
and/or the reaction time of the step B is 1 to 5 hours, preferably 2 to 3 hours.
Further, the purification steps in step B are as follows:
(1) Concentrating the reaction solution under reduced pressure to remove the organic solvent, cooling to precipitate a solid, and performing solid-liquid separation;
(2) Taking the liquid separated in the step (1), extracting with an organic solvent a, taking a water layer, and adjusting the pH value to be alkaline by using a sodium hydroxide solution;
(3) And (3) extracting the liquid obtained in the step (2) with an organic solvent b, then taking an organic layer, and concentrating under reduced pressure to obtain the milnacipran shown in the formula (II).
Further, the organic solvent a is selected from one or more of ethyl acetate, isopropyl acetate, butyl acetate, toluene, dichloromethane and methyl tert-butyl ether; the organic solvent b is one or more selected from ethyl acetate, isopropyl acetate, butyl acetate, toluene, dichloromethane and methyl tert-butyl ether.
Further, the method also comprises the steps of adding the compound shown in the formula (II) into an organic solvent c, and adding an alcohol solvent of hydrogen chloride for reaction to obtain a compound shown in the formula (III); the structural formula of the formula (III) is as follows:
further, the organic solvent c is a mixed solvent composed of esters and alcohol solvents, preferably a mixed solvent composed of isopropyl acetate and isopropanol;
and/or the alcohol solvent of the hydrogen chloride is selected from C1-C4 alcohol solvents, preferably methanol, ethanol, isopropanol and butanol.
Further, the method can also be used for preparing the milnacipran chiral isomer and pharmaceutically acceptable salts thereof, wherein the milnacipran isomer has the structures shown as a formula (IV) and a formula (V); the structural formula of the formula (IV) isThe structural formula of the formula (V) is->/>
Further, the pharmaceutically acceptable salt is selected from hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, adipate, preferably hydrochloride.
The method for preparing the milnacipran and the salt thereof provided by the invention overcomes the technical defects of complex process operation, difficult post-treatment, low product yield, poor product purity, use of highly toxic or explosive reagents and the like in the prior art, effectively controls the generation of impurities, greatly improves the product yield and purity, has the characteristics of environmental protection, safety and economy, is suitable for industrial production, and has wide market application prospect.
The C1-C4 alcohols in the present invention refer to straight or branched chain alcohols having 1 to 4 carbon atoms, such as methanol, ethanol, propanol, isopropanol, n-butanol, etc.
The term "reflux temperature" used in the present invention is understood in the art, and specifically means (the boiling point of the mixed solvent of the organic solvent and water is within 100 ℃ C.)
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention is described in further detail below with reference to examples, but it should not be construed that the scope of the above subject matter is limited to the examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The starting N, N-diethyl-2-phthalimidomethyl-1-phenylcyclopropanecarboxamide (compound I) is a known compound and can be prepared according to literature reports, for example, as described in EP0200638A 1. Other reagents are commercially available.
Example 1 preparation of milnacipran and salts thereof
100g of compound I was added to a mixed solvent of methanol (923 ml)/water (77 ml), and then an aqueous solution of sodium borohydride (20.1 g of sodium borohydride dissolved in 83.4ml of water) was added dropwise, followed by heating to 60 ℃ for reaction. And (5) detecting by TLC to obtain a mixed solution. Cooling the mixed solution to room temperature, adding a hydrochloric acid solution, heating to 60 ℃, and stirring for reaction for 3 hours. The organic solvent was removed under reduced pressure, the residue was cooled to room temperature and stirred to precipitate a solid. Filtering and collecting solid to obtain a crude product of the by-product phthalide. And stirring and extracting the water layer by using toluene, dripping a sodium hydroxide aqueous solution into the water layer, adjusting the pH value to 12-13, extracting by using dichloromethane, reserving an organic layer, and removing the solvent under reduced pressure to obtain a crude product of milnacipran.
Adding isopropanol/isopropyl acetate into the crude milnacipran product, stirring to dissolve, adding 5N isopropanol hydrochloride solution, adjusting the pH value to 3-4, cooling to 10 +/-5 ℃, preserving heat and stirring for 2-3 hours. Filtration and drying gave 65.4g of milnacipran hydrochloride. The yield was 87.1% and the HPLC purity was 99.97%.
Example 2 preparation of milnacipran and salts thereof
100g of the compound I was added to a mixed solvent of isopropanol (1078 ml)/water (612 ml), and then an aqueous solution of potassium borohydride (21.5 g of potassium borohydride dissolved in 89ml of water) was added dropwise, and the mixture was heated to 70 ℃ for reaction. And (5) detecting by TLC to obtain a mixed solution. The temperature of the mixed solution is reduced to room temperature, hydrochloric acid solution is added, and the temperature is increased to reflux and stirring for reaction for 2 hours. The organic solvent was removed under reduced pressure, the residue was cooled to room temperature and stirred to precipitate a solid. Filtering and collecting solid to obtain a crude product of the by-product phthalide. And stirring and extracting the water layer by using toluene, dripping a sodium hydroxide aqueous solution into the water layer, adjusting the pH value to 12-13, extracting by using dichloromethane, reserving an organic layer, and removing the solvent under reduced pressure to obtain a crude product of milnacipran.
Adding isopropanol/isopropyl acetate into the crude milnacipran product, stirring to dissolve, adding 5N isopropanol hydrochloride solution, adjusting the pH value to 3-4, cooling to 10 +/-5 ℃, preserving heat and stirring for 2-3 hours. Filtration and drying gave 66.2g of milnacipran hydrochloride. The yield was 88.1% and the HPLC purity was 100%.
EXAMPLE 3 preparation of milnacipran and its salts
100g of the compound I was added to a mixed solvent of ethanol (666 ml)/water (153 ml), and then an aqueous solution of lithium borohydride (6.2 g of lithium borohydride dissolved in 25ml of water) was added dropwise thereto, followed by heating to reflux. And (5) detecting by TLC to obtain a mixed solution. The temperature of the mixed solution is reduced to room temperature, hydrochloric acid solution is added, and the temperature is increased to reflux and stirring for reaction for 3 hours. The organic solvent was removed under reduced pressure, the residue was cooled to room temperature and stirred to precipitate a solid. Filtering and collecting solid to obtain a crude product of the by-product phthalide. And stirring and extracting the water layer by using toluene, dripping a sodium hydroxide aqueous solution into the water layer, adjusting the pH value to 12-13, extracting by using dichloromethane, reserving an organic layer, and removing the solvent under reduced pressure to obtain a crude product of milnacipran.
Adding isopropanol/isopropyl acetate into the crude milnacipran product, stirring to dissolve, adding 5N isopropanol hydrochloride solution, adjusting the pH value to 3-4, cooling to 10 +/-5 ℃, preserving heat and stirring for 2-3 hours. Filtration and drying gave 67.0g of milnacipran hydrochloride. The yield was 89.2% and the HPLC purity was 99.97%.
Example 4 preparation of milnacipran and salts thereof
100g of the compound I was added to a mixed solvent of n-propanol (964 ml)/water (96 ml), and 126.3g of sodium triacetoxyborohydride was then added thereto, and the mixture was heated to reflux reaction. And (5) detecting by TLC to obtain a mixed solution. The mixed solution is cooled to room temperature, hydrochloric acid solution is added, and the temperature is raised to reflux and stirring for reaction for 3 hours. The organic solvent was removed under reduced pressure, the residue was cooled to room temperature and stirred to precipitate a solid. Filtering and collecting solid to obtain a crude product of the by-product phthalide. And stirring and extracting the water layer by using toluene, dripping a sodium hydroxide aqueous solution into the water layer, adjusting the pH value to 12-13, extracting by using dichloromethane, reserving an organic layer, and removing the solvent under reduced pressure to obtain a crude product of milnacipran.
Adding the milnacipran into propanol/isopropyl acetate, stirring to dissolve, adding 5N isopropanol hydrochloride solution, adjusting the pH to 3-4, cooling to 10 +/-5 ℃, preserving heat and stirring for 2-3 hours. Filtration and drying gave 67.5g of milnacipran hydrochloride. The yield was 89.8% and the HPLC purity was 99.94%.
EXAMPLE 5 preparation of milnacipran and its salts
100g of the compound I was added to a mixed solvent of isopropanol (857 ml)/water (72 ml), and then an aqueous sodium borohydride solution (17.2 g of sodium borohydride dissolved in 72ml of water) was added dropwise thereto, followed by heating to 80 ℃ for reaction. And (5) detecting by TLC to obtain a mixed solution. The mixed solution is cooled to room temperature, hydrochloric acid solution is added, and the temperature is raised to reflux and stirring for reaction for 3 hours. The organic solvent was removed under reduced pressure, the residue was cooled to room temperature and stirred to precipitate a solid. Filtering and collecting solid to obtain a crude product of the by-product phthalide. And stirring and extracting the water layer by using toluene, dripping a sodium hydroxide aqueous solution into the water layer, adjusting the pH value to 12-13, extracting by using dichloromethane, reserving an organic layer, and removing the solvent under reduced pressure to obtain a crude product of milnacipran.
Adding isopropanol/isopropyl acetate into the crude milnacipran product, stirring to dissolve, adding 5N isopropanol hydrochloride solution, adjusting the pH value to 3-4, cooling to 10 +/-5 ℃, preserving heat and stirring for 2-3 hours. Filtration and drying gave 68g of milnacipran hydrochloride. The yield was 90.5% and the HPLC purity was 100%.
EXAMPLE 6 preparation of milnacipran and its salts
100g of the compound I is taken and added into a mixed solvent of ethanol (1285 ml)/water (214 ml), potassium borohydride aqueous solution (43 g of potassium borohydride dissolved in 178ml of water) is added dropwise, and the temperature is raised to 60 ℃ for reaction. And (5) detecting by TLC to obtain a mixed solution. The mixed solution is cooled to room temperature, hydrochloric acid solution is added, and the temperature is raised to reflux and stirring for reaction for 2 hours. The organic solvent was removed under reduced pressure, the residue was cooled to room temperature and stirred to precipitate a solid. Filtering and collecting solid to obtain a crude product of the by-product phthalide. And stirring and extracting the water layer by using toluene, then dripping sodium hydroxide aqueous solution into the water layer, adjusting the pH value to 12-13, extracting by using dichloromethane, reserving an organic layer, and removing the solvent under reduced pressure to obtain a crude product of milnacipran.
Adding isopropanol/isopropyl acetate into the crude milnacipran product, stirring to dissolve, adding 5N isopropanol hydrochloride solution, adjusting the pH value to 3-4, cooling to 10 +/-5 ℃, preserving heat and stirring for 2-3 hours. Filtration and drying gave 68.1g of milnacipran hydrochloride. The yield was 90.6% and the HPLC purity was 99.93%.
EXAMPLE 7 preparation of milnacipran and its salts
100g of the compound I was added to a mixed solvent of ethanol (978 ml)/water (122 ml), and then an aqueous solution of sodium borohydride (12.1 g of sodium borohydride dissolved in 50ml of water) was added dropwise thereto, followed by heating to 40 ℃ for reaction. And (5) detecting by TLC to obtain a mixed solution. The mixed solution is cooled to room temperature, hydrochloric acid solution is added, and the temperature is raised to reflux and stirring for reaction for 3 hours. The organic solvent was removed under reduced pressure, the residue was cooled to room temperature and stirred to precipitate a solid. Filtering and collecting solid to obtain a crude product of the by-product phthalide. And stirring and extracting the water layer by using toluene, dripping a sodium hydroxide aqueous solution into the water layer, adjusting the pH value to 12-13, extracting by using dichloromethane, reserving an organic layer, and removing the solvent under reduced pressure to obtain a crude product of milnacipran.
Adding the milnacipran into butanol/isopropyl acetate, stirring to dissolve, adding 5N isopropanol hydrochloride solution, adjusting the pH to 3-4, cooling to 10 +/-5 ℃, preserving heat and stirring for 2-3 hours. Filtration and drying gave 67.9g of milnacipran hydrochloride. The yield was 90.4% and the HPLC purity was 99.95%.
EXAMPLE 8 preparation of milnacipran and its salts
100g of the compound I was added to a mixed solvent of n-propanol (3750 ml)/water (1250 ml), and then an aqueous solution of lithium borohydride (8.3 g of lithium borohydride dissolved in 34ml of water) was added dropwise, followed by heating to reflux. And (5) detecting by TLC to obtain a mixed solution. The mixed solution is cooled to room temperature, hydrochloric acid solution is added, and the temperature is raised to reflux and stirring for reaction for 3 hours. The organic solvent was removed under reduced pressure, the residue was cooled to room temperature and stirred to precipitate a solid. Filtering and collecting solid to obtain a crude product of the phthalide as a byproduct. And stirring and extracting the water layer by using toluene, dripping a sodium hydroxide aqueous solution into the water layer, adjusting the pH value to 12-13, extracting by using dichloromethane, reserving an organic layer, and removing the solvent under reduced pressure to obtain a crude product of milnacipran.
Adding isopropanol/isopropyl acetate into the crude milnacipran product, stirring to dissolve, adding 5N isopropanol hydrochloride solution, adjusting the pH value to 3-4, cooling to 10 +/-5 ℃, preserving heat and stirring for 2-3 hours. Filtration and drying gave 68.3g of milnacipran hydrochloride. The yield was 90.9% and the HPLC purity was 99.91%.
EXAMPLE 9 preparation of milnacipran and its salts
100g of compound I was added to a mixed solvent of methanol (1107 ml)/water (92 ml), and then an aqueous solution of potassium borohydride (25.8 g of potassium borohydride dissolved in 107ml of water) was added dropwise thereto, followed by heating to 50 ℃ for reaction. And (5) detecting by TLC to obtain a mixed solution. Cooling the mixed solution to room temperature, adding a hydrochloric acid solution, heating to 60 ℃, and stirring for reaction for 2 hours. The organic solvent was removed under reduced pressure, the residue was cooled to room temperature and stirred to precipitate a solid. Filtering and collecting solid to obtain a crude product of the by-product phthalide. And stirring and extracting the water layer by using toluene, dripping a sodium hydroxide aqueous solution into the water layer, adjusting the pH value to 12-13, extracting by using dichloromethane, reserving an organic layer, and removing the solvent under reduced pressure to obtain a crude product of milnacipran.
Adding isopropanol/isopropyl acetate into the crude milnacipran product, stirring to dissolve, adding 5N isopropanol hydrochloride solution, adjusting the pH value to 3-4, cooling to 10 +/-5 ℃, preserving heat and stirring for 2-3 hours. Filtration and drying gave 67.8g of milnacipran hydrochloride. The yield was 90.2% and the HPLC purity was 99.93%.
In conclusion, the yield of the milnacipran hydrochloride prepared by the method can reach 88-90.5%, and the purity can reach 99.9-100%. The method for preparing the milnacipran and the salt thereof effectively controls the generation of impurities, greatly improves the yield and the purity of the product, has the characteristics of environmental protection, safety and economy, is suitable for industrial production, and has wide market application prospect.
Claims (15)
1. A method for preparing 2- (aminomethyl) -N, N-diethyl-1-phenylcyclopropanecarboxamide is characterized in that: the method comprises the following steps:
A. taking a compound (I), and reacting in a solvent in the presence of a reducing agent to obtain a mixed solution; the reducing agent is borohydride;
B. adding acid into the mixed solution obtained in the step A for reaction, and purifying the reaction solution to obtain milnacipran with a structure shown in a formula (II);
2. the method of claim 1, wherein: the solvent in the step A is a mixed solvent of an organic solvent and water;
and/or the volume mass ratio of the mixed solvent to the compound (I) in the step A is 5: 1-20;
and/or the borohydride in the step A is selected from one or more of sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride;
and/or, the molar ratio of the reducing agent to compound (I) in step a is 1:1 to 5;
and/or, the reaction temperature in step a is from 30 ℃ to reflux temperature.
3. The method of claim 2, wherein: the volume mass ratio of the mixed solvent to the compound (I) in the step A is 8-15;
and/or, the molar ratio of the reducing agent to compound (I) in step a is 1.1:1 to 3;
and/or, the reaction temperature in step a is from 40 ℃ to reflux temperature.
4. The method of claim 2, wherein: the organic solvent is selected from alcohols, amides, nitriles and ethers.
5. The method of claim 4, wherein: the organic solvent is selected from one or more of methanol, ethanol, N-propanol, isopropanol, ethylene glycol, N-butanol, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile and tetrahydrofuran.
6. The method of claim 5, wherein: the volume ratio of the organic solvent to the water is 1: 1-30 parts of.
7. The method of manufacturing according to claim 6, characterized in that: the volume ratio of the organic solvent to the water is 3.
8. The method of claim 1, wherein: the acid in the step B is selected from one or more of hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid and perchloric acid;
and/or, the reaction temperature in the step B is 40 ℃ to reflux;
and/or the reaction time of the step B is 1 to 5 hours.
9. The method of claim 8, wherein: the acid in the step B is hydrochloric acid;
and/or, the reaction temperature in the step B is 60 ℃ to reflux;
and/or the reaction time of the step B is 2 to 3 hours.
10. The method of claim 1, wherein: the purification steps in the step B are as follows:
(1) Concentrating the reaction solution under reduced pressure to remove the organic solvent, cooling to precipitate a solid, and performing solid-liquid separation;
(2) Taking the liquid separated in the step (1), extracting with an organic solvent a, taking a water layer, and adjusting the pH value to be alkaline by using a sodium hydroxide solution;
(3) And (3) extracting the liquid obtained in the step (2) with an organic solvent b, then taking an organic layer, and concentrating under reduced pressure to obtain the milnacipran shown in the formula (II).
11. The method for producing as claimed in claim 10, characterized in that: the organic solvent a is one or more selected from ethyl acetate, isopropyl acetate, butyl acetate, toluene, dichloromethane and methyl tert-butyl ether; the organic solvent b is one or more selected from ethyl acetate, isopropyl acetate, butyl acetate, toluene, dichloromethane and methyl tert-butyl ether.
12. The method of claim 1, wherein: the method also comprises the steps of adding the compound shown in the formula (II) into an organic solvent c, and adding an alcohol solvent of hydrogen chloride for reaction to obtain a compound shown in the formula (III); the structural formula of the formula (III) is as follows:
13. the method of manufacturing according to claim 12, wherein: the organic solvent c is a mixed solvent consisting of esters and alcohol solvents;
and/or the alcohol solvent of the hydrogen chloride is selected from C1-C4 alcohol solvents.
14. The method of manufacturing according to claim 13, wherein: the organic solvent c is a mixed solvent consisting of isopropyl acetate and isopropanol;
and/or the alcohol solvent of the hydrogen chloride is selected from methanol, ethanol, isopropanol and butanol.
15. The method according to any one of claims 1-14, wherein: the method can also be used for preparing the milnacipran chiral isomer and pharmaceutically acceptable salts thereof, wherein the milnacipran isomer has the structure shown as a formula (IV) and a formula (V); the structural formula of the formula (IV) isThe structural formula of the formula (V) is
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